Enhanced efficacy of immune checkpoint inhibitors by folate-targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancer
Purpose: The research aims to elucidate the anti-tumor mechanism of the composite multifunctional folate-targeted drug DIFP-FA through sonodynamic therapy (SDT), chemodynamic therapy (CDT), and chemotherapy, as well as its potential to augment immune checkpoint blockade (ICB) therapy in bladder canc...
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Elsevier
2025-04-01
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| Series: | Materials Today Bio |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2590006425001425 |
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| author | Yibo Shi Guangrui Fan Enguang Yang Yuanfeng Zhang Hui Ding Junqiang Tian Liang Cheng Hanzhang Wang Tianzhi Hao Baodui Wang Zhiping Wang |
| author_facet | Yibo Shi Guangrui Fan Enguang Yang Yuanfeng Zhang Hui Ding Junqiang Tian Liang Cheng Hanzhang Wang Tianzhi Hao Baodui Wang Zhiping Wang |
| author_sort | Yibo Shi |
| collection | DOAJ |
| description | Purpose: The research aims to elucidate the anti-tumor mechanism of the composite multifunctional folate-targeted drug DIFP-FA through sonodynamic therapy (SDT), chemodynamic therapy (CDT), and chemotherapy, as well as its potential to augment immune checkpoint blockade (ICB) therapy in bladder cancer (BC). Methods: DIFP-FA was synthesized via the W/O/W method. Its targeting efficacy was assessed using immunofluorescence and small animal imaging. Specific mechanisms were investigated through transcriptome sequencing and validation at both cellular and animal levels was conducted. BC patient-derived organoids (PDOs) and patient-derived tumor xenograft (PDX) models, derived from BC tissues resistant to cisplatin-gemcitabine and tislelizumab, were utilized to evaluate the efficacy of DIFP-FA in combination with SDT/CDT and chemotherapy. A humanized BC-PDX model was constructed to explore the synergistic effect of DIFP-FA with ICB therapy. Results: DIFP-FA, by incorporating doxorubicin and indocyanine green, leverages specific binding to folate receptors for precise targeting and efficient internalization into BC cells. DIFP-FA exhibits pH and ultrasound (US)-responsive cargo release properties, ensuring spatiotemporally controlled release. DIFP-FA induces reduced GPX4 and SLC7A11 expression and ferroptosis through the combination of SDT/CDT and chemotherapy. It also facilitates the transport and release of DAMPs, leading to immunogenic cell death (ICD). PDOs and PDX experiments demonstrated that DIFP-FA + US enhanced T lymphocyte infiltration in tumor tissues. Moreover, its combination with anti-PD-1 therapy effectively cleared immune-tolerant BC. Conclusions: DIFP-FA integrates SDT/CDT with chemotherapy to induce ferroptosis and ICD, efficiently eradicating tumors and activating the immune response, thereby enhancing the efficacy of ICB therapy. |
| format | Article |
| id | doaj-art-533ff9f2744d4936a40d2047e1fa85ce |
| institution | OA Journals |
| issn | 2590-0064 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Materials Today Bio |
| spelling | doaj-art-533ff9f2744d4936a40d2047e1fa85ce2025-08-20T02:00:32ZengElsevierMaterials Today Bio2590-00642025-04-013110158410.1016/j.mtbio.2025.101584Enhanced efficacy of immune checkpoint inhibitors by folate-targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancerYibo Shi0Guangrui Fan1Enguang Yang2Yuanfeng Zhang3Hui Ding4Junqiang Tian5Liang Cheng6Hanzhang Wang7Tianzhi Hao8Baodui Wang9Zhiping Wang10Institute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Gansu Province for Urological Diseases, Gansu Province Clinical Research Center for Urinary System Disease, 730030, Lanzhou, Gansu, ChinaInstitute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Gansu Province for Urological Diseases, Gansu Province Clinical Research Center for Urinary System Disease, 730030, Lanzhou, Gansu, ChinaInstitute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Gansu Province for Urological Diseases, Gansu Province Clinical Research Center for Urinary System Disease, 730030, Lanzhou, Gansu, ChinaInstitute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Gansu Province for Urological Diseases, Gansu Province Clinical Research Center for Urinary System Disease, 730030, Lanzhou, Gansu, ChinaInstitute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Gansu Province for Urological Diseases, Gansu Province Clinical Research Center for Urinary System Disease, 730030, Lanzhou, Gansu, ChinaInstitute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Gansu Province for Urological Diseases, Gansu Province Clinical Research Center for Urinary System Disease, 730030, Lanzhou, Gansu, ChinaThe Legorreta Cancer Center at Brown University, Department of Pathology and Laboratory Medicine, The Warren Albert Medical School of Brown University, Brown University Health, Providence, RI, USAThe Legorreta Cancer Center at Brown University, Department of Pathology and Laboratory Medicine, The Warren Albert Medical School of Brown University, Brown University Health, Providence, RI, USAState Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou University, 730000, Lanzhou, Gansu, ChinaState Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou University, 730000, Lanzhou, Gansu, ChinaInstitute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Gansu Province for Urological Diseases, Gansu Province Clinical Research Center for Urinary System Disease, 730030, Lanzhou, Gansu, China; Corresponding author. Institute of Urology, The Second Hospital of Lanzhou University, Key Laboratory of Gansu Province for Urological Diseases, Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou, China.Purpose: The research aims to elucidate the anti-tumor mechanism of the composite multifunctional folate-targeted drug DIFP-FA through sonodynamic therapy (SDT), chemodynamic therapy (CDT), and chemotherapy, as well as its potential to augment immune checkpoint blockade (ICB) therapy in bladder cancer (BC). Methods: DIFP-FA was synthesized via the W/O/W method. Its targeting efficacy was assessed using immunofluorescence and small animal imaging. Specific mechanisms were investigated through transcriptome sequencing and validation at both cellular and animal levels was conducted. BC patient-derived organoids (PDOs) and patient-derived tumor xenograft (PDX) models, derived from BC tissues resistant to cisplatin-gemcitabine and tislelizumab, were utilized to evaluate the efficacy of DIFP-FA in combination with SDT/CDT and chemotherapy. A humanized BC-PDX model was constructed to explore the synergistic effect of DIFP-FA with ICB therapy. Results: DIFP-FA, by incorporating doxorubicin and indocyanine green, leverages specific binding to folate receptors for precise targeting and efficient internalization into BC cells. DIFP-FA exhibits pH and ultrasound (US)-responsive cargo release properties, ensuring spatiotemporally controlled release. DIFP-FA induces reduced GPX4 and SLC7A11 expression and ferroptosis through the combination of SDT/CDT and chemotherapy. It also facilitates the transport and release of DAMPs, leading to immunogenic cell death (ICD). PDOs and PDX experiments demonstrated that DIFP-FA + US enhanced T lymphocyte infiltration in tumor tissues. Moreover, its combination with anti-PD-1 therapy effectively cleared immune-tolerant BC. Conclusions: DIFP-FA integrates SDT/CDT with chemotherapy to induce ferroptosis and ICD, efficiently eradicating tumors and activating the immune response, thereby enhancing the efficacy of ICB therapy.http://www.sciencedirect.com/science/article/pii/S2590006425001425Composite multifunctional drugSynergistic therapyBladder cancerImmunogenic cell deathImmune checkpoint blockade |
| spellingShingle | Yibo Shi Guangrui Fan Enguang Yang Yuanfeng Zhang Hui Ding Junqiang Tian Liang Cheng Hanzhang Wang Tianzhi Hao Baodui Wang Zhiping Wang Enhanced efficacy of immune checkpoint inhibitors by folate-targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancer Materials Today Bio Composite multifunctional drug Synergistic therapy Bladder cancer Immunogenic cell death Immune checkpoint blockade |
| title | Enhanced efficacy of immune checkpoint inhibitors by folate-targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancer |
| title_full | Enhanced efficacy of immune checkpoint inhibitors by folate-targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancer |
| title_fullStr | Enhanced efficacy of immune checkpoint inhibitors by folate-targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancer |
| title_full_unstemmed | Enhanced efficacy of immune checkpoint inhibitors by folate-targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancer |
| title_short | Enhanced efficacy of immune checkpoint inhibitors by folate-targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancer |
| title_sort | enhanced efficacy of immune checkpoint inhibitors by folate targeted multifunctional drug through synergistic therapy inducing ferroptosis and immunogenic cell death in bladder cancer |
| topic | Composite multifunctional drug Synergistic therapy Bladder cancer Immunogenic cell death Immune checkpoint blockade |
| url | http://www.sciencedirect.com/science/article/pii/S2590006425001425 |
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